Process for isoxazolyl lactones

ABSTRACT

ALTERNATE PROCESS ROUTES TO 7 - (3,5-DISUBSTITUTED-4ISOXAZOLYL)-5-HYDROXY HEPTANOIC ACID LACTONE AND ITS 3AND/OR 4- OPTIONALLY ALKYL SUBSTITUTED ANALOGS ARE DESCRIBED. THE PREPARATIVE ROUTES INVOLVE MULTISTEP PROCEDURES STARTING FROM AMINOETHYL SUBSTITUTED TETRAHYDROPYRANOLS OR THEIR ALKYL SUBSTITUTED ANALOGS. THE FINAL PRODUCT LACTONES ARE KNOWN INTERMEDIATES USEFUL IN THEPREPARATION OF PHARMACOLOGICALLY VALUABLE STEROIDAL COMPOUNDS.

United States Patent O 3,813,411 PROCESS FOR ISOXAZOLYL LACTONES Gabriel Saucy, Essex Fells, N.J., assignor to Hotfmann-La Roche Inc., Nutley, NJ.

No Drawing. Original application Jan. 5, 1970, Ser. No.

811, now Patent No. 3,691,189. Divided and this application June 5, 1972, Ser. No. 259,724

Int. Cl. C07d 85/22 US. Cl. 260-307 H 3 Claims ABSTRACT OF THE DISCLOSURE Alternate process routes to 7 (3,5-disubstituted-4- isoxazolyl)-5-hydroxy heptanoic acid lactone and its 3- and/or 4 optionally alkyl substituted analogs are described. The preparative routes involve multistep procedures starting from aminoethyl substituted tetrahydropyranols or their alkyl substituted analogs. The final product lactones are known intermediates useful in the preparation of pharmacologically valuable steroidal compounds.

This is a division of application of Ser. No. 811 filed Jan. 5, 1970, now US. Pat. No. 3,691,189, issued Sept. 12, 1972.

3,813, 11 1 Patented May 28, 1974 ice BRIEF DESCRIPTION OF THE INVENTION The present invention relates to novel processes useful in the preparation of isoxazolyl substituted lactones of the following formula wherein R R and R are selected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting of hydrogen, lower alkyl, lower alkylaryl and aralkyl.

As used herein the term lower alky is meant to include both branched and straight chain hydrocarbon radicals having from 1 to 7, preferably 1 to 4, carbon atoms. Examples of suitable lower alkyl groups include methyl, ethyl, propyl and butyl. Examples of suitable lower alkylaryl groups include tolyl, xylyl, and the like. The term aralky is meant to include groups such as phenyl lower alkyl, e.g., benzyl and phenylethyl.

The processes of the present invention utilized to prepare compounds of formula I above are more readily understood by reference to the following reaction scheme:

where R R R and R are as above, R taken independently is hydrogen or lower alkyl; R, taken independently is lower alkyl or aralkyl and R and R taken together with the adjacent nitrogen atom form a 5 or 6 membered saturated heterocyclic ring including at the most one additional hetero atom selected from the group consisting of nitrogen and oxygen.

The reaction sequence outlined in the above reaction scheme utilizes either amino ketones of the structure shown in formula II A or vinyl ketones of formula II B as alternative starting materials. It is to be noted that when the amino ketones of formula II A are placed in solution some of this compound is converted to the vinyl ketone of formula II B. Either type of compound or mixtures thereof can be used as starting material. The amino moiety represented by R R N in formula II A can be a lower alkyl amine such as methylamine, ethylamine, propylamine, n-butylamine, hexylamine, etc., preferably n-butylamine; aralkylamines such as a-methyl'benzylamine or amines of complex molecules such as, for example, dehydroabietylamine. Suitable amino groups also include dilower alkylarnines which may optionally contain additional substituents on the alkyl group, e.g., phenyl or cyclic amino groups. Examples of such disubstituted amines include dimethylamine, diethylamine, methylethylamine and the like. Diethylamine is preferred. The amino moiety may also comprise a cyclic group optionally containing an additional hetero atom in the ring. Examples of cyclic amines include pyrrolidine and piperidine. Morpholine is an example of a cyclic amine having an additional hetero atom.

The preparation of starting materials of formula II A is described in some detail in U.S. patent application Ser.

VIII No. 834,547, filed June 18, 1969, inventor Gabriel Saucy, and also in Ser. No. 830,491, filed June 4, 1969, inventor Gabriel Saucy, now US. Pat. No. 3,703,527, issued Nov. 21, 1972. I r

In the aforesaid US. patent application Ser. No. 834,547 the compounds of formula II A are shown to be prepared by the addition of a single mole equivalent of vinyl Grignard to anisoxazolyl substituted lactone at temperatures below about 0 C. followed by addition of the desired amineto the resulting vinyl compound. The preparation of such starting materials of formula II A can be shown, for example, by the following preparation.

A solution of 10.0 g. (44.8 mmoles) of racemic 7-(3,5- dimethyl-4-isoxazolyl)-5-hydroxyheptanoic acid lactone in ml. of freshly distilled tetrahydrofuran was cooled in a Dry Ice-isopropyl alcohol bath under nitrogen. A 25% (weight/volume) solution of vinyl magnesium chloride in tetrahydrofuran (25 ml., 75 moles) was added via sy ringe at a rate such that the temperature remained at approximately 60. The mixture was stirred at 70 for 15 minutes, and then carefully hydrolyzed with 5 m1. of methanol. It was then poured onto a mixture of ice, 24 g. of ammonium chloride and 8 ml. of acetic acid. The resulting solution was extracted with ether and the combined ether solutions were washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine and dried over anhydrous sodium sulfate. After 10 minutes,. 10 ml. of diethylamine was added to the ethereal solution of racemic 9 (3,5 dimethyl 4 isoxazolyl)7- hydroxynon-l-en-3-one. Ten minutes later, solvent removal gave crude racemic 2-(2-diethylaminoethyl)6-[2- (3,S dimethyl 4 isoxazolyl)ethyHtetrahydropyran-Z- 01 as a light yellow oil. This material was taken up in ether and extracted with a total of 100 ml. of 1 N hydro. chloric acid followed by 25 ml. of water. The aqueous solutions were washed with ether and then placed under a layer of ether in an ice bath. The solution was made basic with 3 N sodium hydroxide and then extracted with ether. The ether extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave the purified aforesaid Mannich base as a pale yellow oil.

The starting material may be prepared as follows:

A solution of 320 ml. (325 g.=2.5 moles) of ethyl acetoacetate, 209 ml. (178 g.=2.5 moles) of pyrrolidine and 600 ml. of reagent grade benzene was heated at reflux with azeotropic removal of water for two hours. The benzene was then removed at reduced pressure and the residue was distilled through a -cm. Vigreux column yielding 427 g. of ethyl fi-pyrrolidinocrotonate as a light yellow liquid, B.P. l55-156/ 10 mm.

A solution of the ethyl B-pyrrolidinocrotonate (427 g. =2.33 moles), 190 ml. (182 g., 2.43 moles) of nitroethane and 1300 ml. of triethylamine in 1200 ml. of anhydrous chloroform was cooled in an ice bath under nitrogen. A solution of 235 ml. (393 g.=2.56 mole) of phosphorus oxychloride in 400 ml, of chloroform was added at such a rate that the temperature did not rise above During the addition, which took place over a three-hour period, a viscous orange precipitate formed. This suspension was then stirred under nitrogen overnight. As much solvent as possible was removed at reduced pressure and the resulting red-brown paste was diluted with water and extracted with ether. The ether solutions were washed sequentially with Water, 3 N hydrochloric acid, water, 5% sodium hydroxide solution and Water, and were dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a dark oil which was distilled through a short Vigreux column to give 4- carboethoxy-3,S-dimethylisoxazole as a slightly cloudy, colorless liquid of B.P. 100/ 11 mm.

A suspension of 100 g. (2.63 moles) of lithium aluminum hydride in 2.5 liters of anhydrous ether was stirred under nitrogen as a solution of 272 g. (1.61 mole) of the 4-carboethoxy 3,5 dimethylisoxazole prepared above in 400 ml. of anhydrous ether was added at such a rate as to maintain a gentle reflux. The suspension was stirred at room temperature under nitrogen overnight, during which time an extremely gummy green-gray mass formed in the bottom of the flask. The mixture was cooled in an ice bath and hydrolyzed with saturated aqueous sodium sulfate solution. Anhydrous sodium sulfate was added to dry the ether solution. The salts were removed by filtration and washed carefully with ether and chloroform. Solvent removal from the filtrates, finally at 50/0.1 mm., gave a white crystalline mass. This was triturated with hot ether and then cooled. Filtration gave 3,5 dimethyl 4 hydroxy-methyl-isoxazole as white prisms, M.P. 76.5-77.5 Concentration of the mother liquors gave a second crop of prisms, M.P. 76.5-78.

A solution of 36.3 ml. (60.0 g., 0.5 mole) of thionyl chloride in 50 ml. of methylene chloride was cooled in an ice bath under a very slight negative pressure (for fume removal). A solution of 40.0 g. (0.314 mole) of 3,5-dimethyl 4 hydroxymethylisoxazole in 75 ml. of methylene chloride was added over 2 /2 hours. The resulting solution was stirred at room temperature for 2.0 hours. The solvent was removed at reduced pressure and the residue was distilled to give the desired chloride as a pale yellow'liquid, B.P.91.593/ 15 mm.

A solution of 59.6 g. (0.402 mole) of 4-chloromethyl- 3,5-dimethylisoxazole, prepared as described above, and 116 g. (0.44 mole) of triphenylphosphine in 1 liter of toluene was heated at reflux under nitrogen for 6 hours. The resulting suspension was cooled and filtered. The filtrate was heated at reflux for an additional hours. The precipitate was again removed by filtration and the combined solids were washed well with ether and benzene.

The solvent was removed from the filtrate and the residue was taken up in ml. of fresh toluene and refluxed for an additional 18 hours. Filtration as before gave another small quantity of solid. The combined solids were crystallized from ethanol-ether to give the desired phosphonium salt as a cream-white solid, M.P. 313-316".

A sample from a similar preparation was crystallized again from ethanol-ether to give analytically pure material as small white prisms, M.P. 303-305 (The melting point of this compound is dependent on the rate of heating.)

8.75 g. (0.20 mole) of 55% sodium hydride dispersion was washed under nitrogen with dry pentane to remove the mineral oil. To the flask was added 600 ml. of dimethylsulfoxide (dried over Linde 3A molecular sieves). The resulting suspension was carefully degassed, placed under nitrogen, and heated at 70-75 for 1 hour. The graygreen solution was cooled to approximately 15 and 91.6 g. (0.20 mole) of (3,5-dimethyl 4 isoxazolylmethyl) triphenylphosphonium chloride, prepared as described above, was added in one portion. After approximately 5 minutes, a bright orange precipitate formed in the initially dark red solution. This suspension Was stirred at room temperature for 45 minutes. To the mixture was then added, dropwise via syringe, 25.0 g. (0.223 mole) of acrolein dimer (freshly distilled from and into hydroquinone) at such a rate that the temperature remained less than 30 (10-15 minutes with water bath cooling). The light orange-brown solution was stirred at room temperature for 20 minutes, and then at 6065 for 3 hours. (In some experiments, the mixture became very black during the heating period.) The reaction mixture was cooled, poured onto ice, and slurried until all of the dark oil solidified. The suspension was filtered and the filter cake was washed well with pentane. The filtrates were extracted with pentane and the pentane solutions were washed with water and brine and dried over anhydrous sodium sulfate. Solvent removal gave a slightly orange oil which was distilled from a small quantity of anhydrous potassium carbonate to give the desired product as a colorless liquid, B.P. 8385/0.1 mm.

To a solution of 33.5 g. (0.163 mole) of 3,5-dimethyl-4- (3,4-dihydro-ZH-pyran-2-ylvinyl)-isoxazole, prepared as described above, in 400 ml. of dioxane, was added 400 ml. of 1 N sulfuric acid and the cloudy solution, which "soon cleared, was stirred at room temperature for 1 hour.

The mixture was poured into 2 liters of saturated aqueous sodium bicarbonate solution and extracted well with ether. The ether extracts were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave a colorless oil, the infrared spectrum of which indicated that complete hydration of the enol ether had taken place. This material was taken up in 2 liters of benzene and placed under nitrogen. To the fiask was added 400 g. of manganese dioxide and the resulting suspension was stirred at room temperature for 40 hours. The manganese dioxide was removed by filtration and carefully washed with fresh benzene. Solvent removal from the filtrate gave 23 g. of yellow solid. Two crystallizations of this material from benzene-ether gave the desired lactone as a cream-white powder, M.P. 90.0-91.5

A mixture of 16.80 g. (76.0 mmoles) of racemic 7-(3,5- dimethyl 4 isoxazolyl) 5 hydroxy-A -heptenoic acid lactone prepared as above, 400 ml. of ethylacetate and 500 mg. of 10% palladium on carbon was hydrogenated at room temperature and atmospheric pressure. Uptake (1.25 x theoretical) was rapid and ceased after 2 hours. The catalyst was removed by filtration and washed with fresh ethyl acetate. Solvent removal gave a colorless oil which was crystallized from ether at -20 to give the desired product as white microprisms of M.P. 61-62.5.

To a solution of 1.0 g. (4.88 mmoles) of 3,5-dimethyl-4- '(3,4-dihydro-2H-pyran-2-ylvinyl)isoxazole, prepared as described above, in 10 ml. of ethanol was added 5 drops of 1 N sulfuric acid. The solution was stirred at room temperature overnight, poured into excess saturated aqueous sodium bicarbonate solution, and extracted with ether. The ether extracts were washed with water and saturated brineand dried over anhydrous sodium sulfate. Solvent removal gave 1.25 g. of pale yellow liquid whose infrared spectrum indicated that formation of racemic 3,5-dimethyl-4-(G-ethoxytetrahydropyran 2 ylvinyl)-isoxazole was complete. This material was taken up in 10 ml. of ethyl acetate. To this solution was added 25 mg. of 10% palladium on carbon and the resulting mixture was hydrogenated at room temperature and atmospheric pressure. After 2 hours, one equivalent of hydrogen had been consumed and uptake ceased. The catalyst was removed by filtration and washed with fresh ethyl acetate. Solvent removal from the filtrates gave 1.28 g. of racemic 3,5-dimethyl 4 (6 ethoxytetrahydropyran-Z-ylethyl)-isoxazole as a colorless oil whose infrared spectrum indicated that the hydrogenation was complete. This crude acetal was taken up in 20 ml. dioxane. To the flask was added 10 ml. of 1 N sulfuric acid and the resulting solution was stirred at room temperature for 4 hours. It was then poured into excess saturated aqueous sodium bicarbonate solution and extracted with ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave racemic 3,5-dimethyl 4 (6 hydroxytetrahydropyran-2-ylethyl)-isoxazole as a viscous oil. The crude hemiketal was taken up in 25 ml. of 1,2-dichloroethane, degassed and placed under nitrogen. To the flask was added 7.5 g. of manganese dioxide and the resulting suspension was stirred at room temperature overnight. The manganese dioxide was removed by filtration and washed with fresh solvent. Solvent removal from the filtrates gave a pale yellow resin which was crystallized from other at -20 C. to ive the desired lactone, 3,5 dimethyl 4 (G-hydroxytetrahydropyran 2 ylethyl) isoxazole, as a White solid of MP. 60-62.

A solution of 3,5 dimethyl 4 (G-hydroxytetrahydropyran-Z-ylethyl)-isoxazole, prepared as described above in 600 ml. of acetone was cooled in an ice bath as 400 ml. of Jones reagent was added dropwise over a 1.0 hour period. The resulting suspension was stirred at room temperature overnight. Saturated sodium bisulfite solution was added to destroy the excess oxidizing agent and most of the acetone was removed at reduced pressure. The residue was diluted with water, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solution were washed with brine and then with excess saturated aqueous sodium bicarbonate solution. The sodium bicarbonate solutions were washed with ether, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a pale yellow resin. Crystallization of this material from ether gave two crops of racemic 7-(3,5 dimethyl 4 isoxazolyl) 5 oxo-heptanoic acid as a fine white powder, M.P. 61.5-63.5

A solution of the keto acid prepared above (41.2 g., 0.178 mole) in 600 m1. of isopropyl alcohol was placed under nitrogen. To this solution was carefully added 10.0 g. (0.296 mole) of sodium borohydride. After the initial vigorous reaction had subsided, the cloudy solution was heated at reflux overnight. A major portion of the solvent was then removed at reduced pressure. The residue was diluted with water, acidified with l N hydrochloric acid, saturated with salt, and extracted with ether. The other solutions were washed with brine and dried over anhymaterial was heated to 220/0.3 mm., at which time a colorless liquid rapidly distilled. Crystallization from ether gave the desired lactone as white prisms, M.P. 61- 63 In step (a) compounds of formula H A and/or II B are reacted with an a -diketone compound of the follow-. ing formula where R and R, are as above. I

This reaction is conveniently conducted at a temperature in the range of from about 0 to 150 C., most preferably at the reflux temperature of a suitably high boiling inorganic solvent. Suitable inert organic solvents for this purpose include aromatic hydrocarbons, most prefer ably xylene or toluene. The reaction product obtained is a compound of formula III which as indicated in the above reaction scheme is believed to exist as a complex equilibrium mixture containing the two structures shown. Infrared and nuclear magnetic resonance spectra indicate that the predominate form in this equilibrium is the form indicated by subformula III A. However, it is under stood that this equilibrium can be shifted by changes in the,

conveniently conducted at a temperature in the range of from about 0 to 100 C., most preferably at about room temperature. Suitable salts of hydroxylamin'e include the mineral acid salts of hydroxylamine, most preferably the hydrochloride salt. The reaction is most desirably con-f ducted in the presence of an organic base, most preferably a tertiary amine such as a tri-lower alkylamine, e.g.,

triethylamine or pyridine.

In step (c) the bis-oxime of formula IV is converted by heating to the isoxazole oxime of formula V. Suitable solvents for use in this transformation step include organic solvents having a boiling point above about 50 C., most preferably above about C. and include, for example,

aromatic hydrocarbons such as benzene, toluene and xylene or halogenated aromatic hydrocarbons such as chlorobenzene. Generally, the reaction is most desirably conducted at the reflux temperature of the solvent medium. Compounds of formula Vneed, not be purified prior to undergoing the next process step in the reaction scheme.

In step (d) compounds of formula V are subjected to aqueous acid hydrolysis to yield compounds of .formula VI represented by the tautomeric equilibrium structure. Particularly suitable aqueous acids for use in this hydrolysis step include the mineral acids, e.g., sulfuric acid and hydrochloric acid. The hydrolysis may also be performed in the presence of a hydroxylamine scavenger, e.g.,

pyruvic acid. A most preferred aqueous acid for this purpose is dilute sulfuric acid, e.g., 1 N sulfuric acid. The

hydrolysis reaction may conveniently be conducted at a temperature in the range of from about 0 to 80 C., most preferably at about room temperature. The reaction may also be conducted in the presence of an added inert organic solvent. Suitable solvents for this purpose include ketones such as acetone, methylethyl ketone and the like; lower alkanols such as methanol and ethanol; cyclic others such as tetrahydrofuran, dioxane, etc. Acetone is the solvent of preference for this purpose.

The compounds of formula VI may be converted into the desired compounds of formula I bymeans of two alternative pathways. In the first of these pathways the compounds of formula VI are oxidized in step (g) to yield the isoxazolyl keto acid of formula VII. This oxidation reaction is conducted in the presence of a chemical oxidizing agent such as, for example Jones reagent, e.g., chromium trioxide in sulfuric ;acid and acetone at a temperature in the range of from about 10 C. to +50 C., most desirably the aforesaid oxidation step can be prac ticed on the reaction mixture obtained from hydrolysis step (d) above without necessitating isolation or purification of the compounds of formula VI produced therein. Thus, in a most preferred embodiment of this process step the oxidizing agent, e.g., Jones reagent is added directly to the reaction mixture obtained from step (d) subsequent to the completion of the hydrolysis reaction.

Compounds of formula'VII are then reduced and cyclized to the desired compounds of formula I via process step (f) in a manner known per se. The reduction of the keto group of compounds of formula VII may be accomplished utilizing conventional reducing agents for this purpose. Reducing agents'useful in this process step includethe complex metal hydrides,e.g., alkali metal borohydrides, preferably sodium borohydride. The reduction can also be effected using catalytic hydrogenation such as withRaney-nickel as catalyst in a lower alkanol at a temperaturein the range of from about to 100 C., preferably at about room temperature at normal pressure.

The borohydride reduction reaction is conveniently conducted in a suitable inert organic solvent such as, for example, lower alkanols, such as methanol, ethanol or preferably isopropanol; aqueous cyclic ethers such as tetrahydrofuran or dioxan. The borohydride reduction reaction is conducted at a temperature in the range of from about 50 to +50 0., most preferably in the range of from about to +25 C.

The cyclization step can proceed spontaneously in the above reaction media, but most preferably can be promoted by subsequent heating, e.g., at reflux in an aromatic hydrocarbon, e.g., toluene or by addition of an acid, e.g., a mineral acid.

In an alternate and preferred route, compounds of formula VI are converted to compounds of formula I by means of a series of novel intermediate reaction steps. Thus, in step (g) compounds'of formula VI are treated with an oxidizing reagent comprising silver carbonate at elevated temperatures to yield the keto aldehyde of formula VIII. This reaction is conveniently conducted in an inert organic solvent; most preferably an aromatic hydrocarbon, e.g., toluene,xylene or benzene. The reaction is run at a temperature in the range of from about 20 C. to the reflux temperature of the reaction medium, most preferably at the reflux temperature of the reaction medium.

The keto aldehyde of formula VIII may then be converted to the desired product of formula I by treating the former compound with a metal alkoxide, preferably at the same conditions employed in step (g). It is therefore desirable to conduct both steps concurrently in a single reaction vessel. Suitable metal alkoxides useful in the practice of step (h) include the aluminum lower alkoxides and sodium lower alkoxides, e.g., aluminum isopropoxide and sodium methoxide. Aluminum isopropoxide is the agent of greatest preference for this purpose.

Compounds of the formulae III, IV, V, VI, and VIII above are novel intermediates and as such form a part of the present invention Preferred embodiments of the process and compound aspects of the present invention are obtained when R, and R both are hydrogen, R and R both are lower alkyl, but most preferably methyl, and R and R both are lower alkyl, most preferably ethyl.

The conversion of compounds of formula I into 19-nor steroids of known pharmacological value is described in detail'in US. patent application Ser. No. 778,314, filed Nov. 22, 1968, inventors Gabriel Saucy-and John William Scott now US. Pat. No. 3,700,661, issued Oct. 24, 1972.

The present invention will be more clearly understood by reference to the following examples.

1 0 EXAMPLE 1 Preparation of 2-(Z-diethylaminoethyl)-2-hydroxytetrahydropyran In a 3-liter, three-necked flask fitted with a mechanical stirrer and reflux condenser there was dissolved 25.2 g. of 6-heptene-1,5-diol in 700 ml. of 1,2-dichloroethane. The solution was maintained under a nitrogen atmosphere and m1. of diethylamine and 208 g. of activated manganese dioxide were added With cooling from an ice bath. The reaction mixture was then stirred at room temperature un der an atmosphere of nitrogen for one day. The solution was filtered and the filter was washed well with benzene. The combined filtrates were evaporated at 40 C. under 20 mm. Hg and finally at 1 mm. Hg to yield 34.6 g. of the above product as a dark brown oil.

A total of 31.6 g. of the above crude material was dissolved in 50 ml. of ethyl acetate and treated with 200 ml. of 1.2 N hydrochloric acid. After extracting the aqueous phase 3 times with 100 ml. each the portions of ethyl acetate, the aqueous phase was brought to pH 11 with ice cooling using 30 ml. of 1 N sodium hydroxide. The resulting solution was extracted with 4 300 ml. each of benzene and the combined benzene layers were dried over sodium sulfate, filtered and then evaporated in vacno to dryness. Pure 2-(2-diethylaminoethyl)-2-hydroxytetrahydropyran was obtained as an oil in a yield of 25.3 g. (71% A sample was further purified by passing through a column of alumina (III) and eluting with benzene. Evaporation of the solvent yielded an analytical sample of the aforesaid pure product.

C H NO (201.30)

Calcd.: C, 65.63; H, 11.52; N, 6.96 Found: C, 65.80; H, 11.52; N, 6.69.

EXAMPLE 2 3-acetyl-10-hydroxy-2,6-decanedione In a 500 ml. round bottom flask fitted with a regular condenser there was added 25.3 g. of 2-(2-diethylaminoethyl)-2-hydroxytetrahydropyran dissolved in 250 ml. of toluene and 25 ml. of 2,4-pentanedione. The mixture Was stirred and refluxed under nitrogen for six and one-half hours. It was then cooled to room temperature and concentrated at approximately 50 C. at 20 mm. Hg and finally at 1 mm. Hg at approximately 35 C. There was obtained 31.5 g. of crude product as a yellowish oil. A sample of the crude material was chromatographed on silica gel and crystallized from ether to give pure 3-acetyl-10-hydroxy- 2,6-decanedione, M.P. 6568 C.

C H O (228.28)

Calcd.: C, 63.13; H, 8.83 Found: C, 62.86; H, 8.82.

EXAMPLE 3 Preparation of 1-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy- 3-hydroxyimino-heptane and refluxed for three and one-half hours with stirring.

After evaporating the solvent at about 50 C. under 20 mm. Hg, the residue obtained was taken up in 300 ml. of chloroform and extracted with 2 100 ml. of distilled water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated at 40 C. under 20 mm. Hg and finally under 1 mm. Hg to afford 25.8 g. of crude 1- 3,5 -dimethyl-4-isoxazolyl) -7-hydroxy-3-hydroxyimino-heptane as a dark brown oil. A sample of this material was chromatographed on silica gel using 1:1 etherethyl acetate to elute the product as an oil analytically pure form.

C H N O (240.30)

Calcd.: C, 59.98; H, 8.39; N, 11.66 Found: C, 59.78; H, 8.69; N, 11.66.

EXAMPLE 4 Preparation of 1-(3,5-dimethyl-4-isoxazolyl)-7- hydroxy-3-heptanone A total of 25.8 g. of crude 1-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-3-hydroximino-heptane was dissolved in 200 ml. of acetone containing 26 ml. of 1 N sulfuric acid and stirred at room temperature overnight. The resulting solution contains crude 1-(3,5-dimethyl 4 isoxazolyl)-7-hydroxy-3-heptanone and may be utilized per se in further transformation steps.

An analytical sample of the above product may be obtained by neutralization of the above reaction mixture with sodium carbonate, evaporation of the solvent, extraction with chloroform and separation and evaporation of the organic phase. The residue obtained is crystallized from ether-hexane to yield pure product, M.P. 5153 C.

c H No, 225.27

Calcd.: C, 63.98; H, 8.50; N,6.22 Found: C, 64.18; H, 8.78; N, 6.22.

EXAMPLE 5 Preparation of 7-(3,5-dimethyl-4-isoxazolyl)-5-oxoheptanoic acid To the reaction mixture containing 1-(3,5-dimethyl-4- isoxazolyl)-7-hydroxy-3-heptanone obtained in Example 4 there was added dropwise 60 ml. of Jones reagent at 20 C. with stirring. After stirring at room temperature for an additional two hours, the mixture was cooled with ice and a solution of sodium bisulfite was added until the solution turned green. The solvent was evaporated at 40 C. and at 20 mm. Hg and the residue was saturated with solid sodium chloride and extracted with 4 x 100 ml. of ethyl acetate. The combined organic extracts were washed with 2x 100 ml. of saturated sodium chloride solution. The organic phase was extracted with 4X 70 ml. of percent sodium carbonate solution. The aqueous extracts were combined and acidified with dilute sulfuric acid to a pH of 1. Extraction with 3 X 200 ml. of ethyl acetate followed by washing with saturated sodium chloride solution (100 ml.), drying over anhydrous sodium sulfate, filtration and evaporation of the solvents at 40 C. under 20 mm. Hg and finally under 1 mm. Hg yielded 11.1 g. of crude 7-(3,5- dimethyl-4-isoxazolyl)-5-oxo-heptanoic acid as a brown oil. Two crystallizations from ethyl-ether yielded pure product, M.P. 58-61 C.

EXAMPLE 6 Preparation of 7-(3,5-dimethyl-4isoxazolyl)-5- oxoheptanal Calcd.: C, 64.55; H, 7.68; N, 6.27 Found: C, 64.53; H, 7.63; N, 6.33.

EXAMPLE 7 Preparation of 7-(3,5-dimethyl-4-isoxazolyl) 5-hydroxyheptanoic acid lactone (A) From 7 (3,5 dimethyl-4-isoxazolyl) 5-oxohep tanal.A total of 1.00 g. of crude 7-(3,5-dimethyl-4-. isoxazolyl)-5-oxoheptanal was allowed to react for 21 2 hours with 200 mg. of aluminum isopropoxide in .9 of refluxing toluene. The reaction mixture was filtered and the filter Washedwith benzene. The combined organic solvents were evaporatedin vacuo to git/e079 g. of crude,

7( 3,5 di'methyl-4-isoxazolyl)-5-hydroxy-heptenoic a'cid lactone the identity of which was established by compari, son of thin-layer chromatogram, infrared spectrum and. gas chromatographic analysis with authentic materials.

(B From 7-hydroxy-1- (3 ,5-dimethyl-4-isoxazolyl) 3-;

heptanone.--A total of 50.3 mg. of 7-hydroxy-1-(3,S-di-.

methyl-4-isoxazolyl)-3heptanone was; dissolved in 5 ml.

of toluene and allowed to react for 8 hours at reflux under an atmosphere of nitrogen with 500 mg.of the silver carbonate-Celite reagentidentified inExample 6.and 50 mg.

of aluminum isoxpropoxide. A total of 25.4 mg. of an oil was obtained after workup as inA above. This oil was shown by gas chromatographic analysis to contain 68.5 percent of 7-( 3,5-dimethyl-4-isoxazolyl)'-5-hydroxy-.

heptenoic acid lactone. v I k I I V (C) From 7 (3,5-dimethyl-4-isoxazolyl)-5+oxo-heptanoic acid-A solution containing 41.2 g. of 7-(3 ,5-d imethyl-4-isoxazolyl)-5 oxo-heptenoic acid in '600 ml. oft isopropyl alcohol was placed under nitrogen. To this.

of solvent at reduceclpressure gave 7-(3,5-dimethyl-4 l isoxazolyl-S-hydroxyheptanoic acid. This material was heated to 220 C./0.3 mm. Hg, at which time a colorless liquid was rapidly distilled. Crystallization from ether gave 7 (3,5-dimethyl-4isoxazolyl)-5-hydroxy-heptanoic acid lactone as white prisms, M.P. 61- 63" C.

I claim: 1. A process for the formula an ll wherein R R and R4 are selected from the group'cOnsisting of hydrogen" and C lower alkyl and R is lower alkyl which process comprises in combination A. reacting a compound of the formula i-W p where R R R and R are as above preparation of a compound ofthe with Jones reagent so as to form a compound of the formula COOH VII

where R R R and R are as above and B. reducing said compound of formula VII with a complex metal hydride or by catalytic hydrogenation and then allowing the reduced product to cyclize in the reaction medium.

2. The process of claim 1 wherein R and R both are hydrogen; R and R both are methyl; Jones reagent is utilized as the oxidizing agent in step A; and sodium borohydride is utilized as the reducing agent in Step B.

3. The process of claim 1 wherein said reduced product of step B is cyclized in a subsequent step by refluxing in an aromatic hydrocarbon solvent or by addition of a mineral acid.

References Cited FOREIGN PATENTS 3,818,698 9/1963 Japan 260307 H OTHER REFERENCES Morrison, Organic Chemistry, Allyn & Bacon, Boston, 1959, QD251M72.

DONALD G. DAUS, Primary Examiner R. D. MCCLOUD, Assistant Examiner US. Cl. X.R. 

